Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation

Abstract

Endogenous metabolites play essential roles in the regulation of cellular identity and activity. Here we have investigated the process of oligodendrocyte precursor cell (OPC) differentiation, a process that becomes limiting during progressive stages of demyelinating diseases, including multiple sclerosis, using mass-spectrometry-based metabolomics. Levels of taurine, an aminosulfonic acid possessing pleotropic biological activities and broad tissue distribution properties, were found to be significantly elevated (~20-fold) during the course of oligodendrocyte differentiation and maturation. When added exogenously at physiologically relevant concentrations, taurine was found to dramatically enhance the processes of drug-induced in vitro OPC differentiation and maturation. Mechanism of action studies suggest that the oligodendrocyte-differentiation-enhancing activities of taurine are driven primarily by its ability to directly increase available serine pools, which serve as the initial building block required for the synthesis of the glycosphingolipid components of myelin that define the functional oligodendrocyte cell state.

Metabolomics activity screening for identifying metabolites that modulate phenotype

“…Metabolites that are differentially regulated can be identified using databases (e.g., METLIN (https://metlin.scripps.edu), the human metabolome database (HMDB; http://www.hmdb.ca), and LIPID MAPS; http://www.lipidmaps.org/) 10–12 , whose features and limitations have been reviewed 13 . The main advantage of untargeted LC-MS metabolomics is that it is an unbiased way to identify metabolites associated with a particular condition, whether it is stem-cell differentiation 14,15 , immune-cell activation 16–19 , remyelination in multiple sclerosis 20 , chronic pain 21 , or type 2 diabetes 22,23 , to name but a few of the hundreds of examples that have been reported.…”

“…and colleagues) 29 , molecular origins of chronic pain (G.S. and colleagues) 21 , and, most recently, remyelination for neuron repair (J.R.M.-B., G.S, and colleagues) 20 . Comparatively, though, little effort has been dedicated to examining the activity of these biomarkers.…”

“…We (J.R.M.-B., G.S., and collaborators) 20 have also used MAS to analyze oligodendrocyte precursor cell (OPC) differentiation in multiple sclerosis, an autoimmune disease characterized by demyelination of axons and neuronal dysfunction. Disease remission in multiple sclerosis is dependent on remyelination, which involves the differentiation of OPCs and leads to the formation of mature oligodendrocytes 33 .…”

“…We used MS-based metabolomics to investigate how endogenous metabolites play a role in the process of OPC differentiation 20 . Among other related metabolites, taurine, an amino sulfonic acid, was found to be significantly elevated (~20-fold) over the course of in vitro oligodendrocyte differentiation (Fig.…”

“…When exogenously added, this lipid amplified microbicidal capacity of macrophages in response to the fungal stimulus zymosan 16 . ( e ) Taurine, that was observed to be highly upregulated during OPC differentiation, enhanced the effect of a novel drug treatment (miconazole) to induce OPC differentiation into mature oligodendrocytes, a promising cell target for multiple sclerosis treatment 20 .…”